Linear polysaccharide constituted of repetitive units of D-glucuronic acid and N-acetyl-D-glucosamine, the hyaluronic acid is found in the extra-cellular matrix of numerous connective tissues (skin, tendons, muscles, etc), more precisely as a polyanion called “hyaluronane”.
In the skin for instance, the hyaluronic acid (hereafter “HA”) is one of the major components. An important amount is indeed found in the dermal and epidermal extra-cellular matrix. Its hydrophilic and viscoelastic properties make it an essential actor in the preservation of moisturizing, volume and cutaneous cohesion.
The HA synthesized by fibroblasts and keratinocytes (hereafter “native HA”) mainly exists as polymers of very high molecular weight (>to 2.000 kDa) able even to reach 4.000 kDa with a chain of 10.000 disaccharides (Hascall V. C. and al., GlycoForum/Hyaluronan Today (1997), chapter 1).
However, the native HA is submitted in skin to a set of physiological damage reactions, notably enzymatic, called catabolism that aims at reducing it in smaller fragments (hereafter “fragmented HA”). Since several years, research teams turned their attention towards the catabolism of HA and its consequences in the organism. And the conclusion of all these works is in general unanimous, that is to say that the fragmented HA has a different behavior from the native HA, and that according to the size of fragments, in other words their molecular weight, it is observed different biological effects, and even opposite (Noble P. W., Matrix Biol. (2002), vol. 21, pp. 25-29; Asari A., GlycoForum/Hyaluronan Today (2005), chapter 29 and quoted references).
It is thus reported for HA fragments said of high molecular weight an effect on regeneration and healing, an important role as regulator of the inflammatory process, but also an immunosuppressive effect. On the other hand, oligomers said of low weight are presented as entities able to activate the immune cells and to deliver endogenous signals with respect to stress, but also to be powerful inducers of inflammation and angiogenesis (Stern R., Clin. Dermatol. (2008), vol. 26, pp. 106-122; Krasinski R. et al., Postepy Hig. Med. Dosw (2007), vol. 61, pp. 683-689).
More precisely concerning skin, it is reported a stimulation of the keratinocytes' proliferation in culture, for fragments called “of intermediate size” with a molecular weight between 50 and 400 kDa (Kaya G. and al., PLoS Medicine (2006), vol. 3, pp. 2291-2303). These effects are also observed after topical application of a preparation based on HA fragments of molecular weight between 50 and 750 kDa (described “of low molecular weight” in the specification of FR 2865651 application). This advantageous property, notably synonymous of a better barrier function of the skin with a thickness of the epidermis increased, would be however not anymore observed with small HA fragments lower than 50 kDa (Kaya G. and al., PLoS Medicine (2006), vol. 3, pp. 2291-2303).
Although it has been considered for a long time that a transcutaneous crossing of HA, for a benefit beyond the simple surface of the skin and the cornea layer, could be only considered for fragments of HA with very low molecular weight (< to 50 kDa, Tammi R. and al., J. Invest. Dermatol. (1991), vol. 97, pp. 126-130), it is henceforth mentioned a diffusion capacity in the epidermis for HA fragments of definitely higher size, namely for fragments from 360 to 400 kDa (Brown T. J. and al., J. Invest. Dermatol. (1999), vol. 113, pp. 740-746) or else for the above mentioned intermediate fragments (50-400 kDa). This diffusion would even go as far as able to reach the dermis with also the above referred topical preparation based on HA (50-750 kDa).
In the cosmetic area and especially the one combating cutaneous aging, it can be advisable to bring topically to the skin some fragmented hyaluronic acid with appropriate size, and this, in order to fight against aging effects or extrinsic factors (free radicals, ultra-violet radiation, pollution, etc). It is indeed admitted that aging or ultra-violet radiations influence the HA catabolism and the release of fragments, and can result in a lower intracellular production and a more uneven layout (Meyer and al., J. Invest. Dermatol. (1994), vol. 3, pp. 385-389). However, a cosmetic application would not satisfy with unwanted secondary effects, such as here-above mentioned pro-inflammatory effect for small fragments of hyaluronic acid.